For some years aminoalkylidene substituted thiaxanthenes having a substituent in position 2 of the phenyl rings have been found useful as tranquilizers and neuroleptics in the treatment of psychoses, and among them may be mentioned chlorprothixene (trans-9-(3-dimethylaminopropylidene)-2-chloro-thioxanthene), clopenthixol (9-[3(4-(2-hydroxyethyl)piperazinyl-(1))-propylidene]-2-chloro-thioxanthen e) and flupenthixol (9-[3-(4-(2-hydroxyethyl)piperazinyl-(1) )-propylidene ]-2-trifluoromethyl-thioxanthene.
A reliable method useful for the preparation of these thioxanthenes consists in the addition of an amine to a abnormalies of animals therewith, and pharmaceutical compositions comprising such novel compounds as active ingredients. Other objects will be apparent to one skilled in the art and still other objects will become apparent hereinafter.
For some years aminoalkylidene substituted thiaxanthenes having a substituent in position 2 of the phenyl rings have been found useful as tranquilizers and neuroleptics in the treatment of psychoses, and among them may be mentioned chlorprothixene (trans-9-(3-dimethylaminopropylidene)-2-chloro-thioxanthene), clopenthixol (9-[3(4-(2-hydroxyethyl) piperazinyl-(1))-propylidene]2-chloro-thioxanthene) and flupenthixol (9-[3-(4-(2-hydroxyethyl)piperazinyl-(1))-propylidene]-2-trifluoromethyl-t hioxanthene. A reliable method useful for the preparation of these thioxanthenes consists in the addition of an amine to a 9-allylidene-thiaxanthene whereby aminopropylidenethioxanthenes are obtained in satisfactory yields when the reaction is carried out at elevated temperatures. The reaction may be illustrated by the following reaction scheme: ##STR2##
It has now surprisingly been found according to the method of the present invention that when a compound of Formula II wherein Y, R.sup.1 and R.sup.2 are as previously defined is treated with an amine of the formula: ##STR3## about room temperature and with exclusion of light there is obtained a compound of Formula I which may be isolated as the free base or in the form of a non-toxic acid addition salt, and in the event where the compound of Formula I contains a free hydroxyl group, if desired, reacting with a reactive derivative of an aliphatic carboxylic acid having from 1- 17 carbon atoms inclusive, and isolating the ester formed as the free base or a non-toxic acid addition salt thereof. The addition is preferably carried out in an inert solvent such as an alcohol, for example ethanol, and with excess of the amine of Formula III.
The starting compounds of Formula II are prepared by reacting a xanthene of thioxanthene of formula: ##STR4## wherein Y, R.sup.1 and R.sup.2 are as previously defined, with allyl magnesium bromide, hydrolysing the Grignard complex formed, and dehydrating the xanthenol or thioxanthenol in wellknown manner, for example as described in U.S. Pat. No. 3,116,291.
Preferred compounds of this invention are those of Formula I in which Y is sulfur, R.sup.1 is chlorine, trifluoromethyl or dimethylsulfamoyl at position 2, R.sup.2 is hydrogen or fluorine at position 6 and R.sup.3 and R.sup.4 together with the nitrogen atom form a 2-hydroxyethyl substituted piperazine ring optionally esterified with an aliphatic carboxylic acid residue with from 1-17 carbon atoms inclusive.
This invention also includes pharmaceutically acceptable salts of the bases of Formula I with non-toxic organic and inorganic acids. Such salts are easily prepared by methods known to the art. The base is reacted with either the calculated amount of organic or inorganic acid in an aqueous miscible solvent, such as acetone or ethanol, with isolation of the salt by concentration and cooling or an excess of the acid in aqueous immiscible solvent, such as ethyl ether or chloroform, with the desired salt separating directly. Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, embonic, succinic, bis methylene-salicyclic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzene sulfonic and theophylline acetic acids as well as the 8-halotheophyllines, for example 8-bromotheophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. Of course, these salts may also be prepared by the classical method of double decomposition of appropriate salts which is well known to the art.
The new compounds of Formula I may exist in the form of two geometric isomers. The individual isomers have the valuable pharmacodynamic effects in varying degrees. The single isomers and their isolation fall likewise within the scope of the present invention.
The compounds of Formula I and the non-toxic acid addition salts thereof may be administered both orally and parenterally, for example in the form of tablets, capsules, powders, syrups or solutions for injection.
When preparing esters of compounds of Formula I having a hydroxy group, i.e., when R.sup.3 and R.sup.4 taken together with the nitrogen atom form a piperazine or piperidine ring substituted in the 4-position with a 2-hydroxyethyl group, the reactive derivative of the aliphatic carboxylic acid in question is advantageously an acid halide or acid anhydride of the acid. As acids useful for this purpose may be mentioned acetic acid, propionic acid, butyric acid, valeric acid, enenthic acid, decanoic acid, hendecanoic acid and palmitic acid. Other acids may, however, be used equally well.